WO2013037843A1

WO2013037843A1 - Formulation for the treatment of benign prostate hyperplasia

Info

Publication number: WO2013037843A1
Application number: PCT/EP2012/067865
Authority: WO
Inventors: Nicholas John Larkins
Original assignee: AKL INFLAMMATORY Ltd
Current assignee: AKL INFLAMMATORY Ltd
Priority date: 2011-09-12
Filing date: 2012-09-12
Publication date: 2013-03-21
Anticipated expiration: 2014-03-12
Also published as: GB201115757D0

Abstract

Compositions for use in the treatment of benign prostate hyperplasia (BPH), the compositions comprising apocynin and one or more compounds selected from the group consisting of paeonol, a pharmaceutically acceptable salt or ester thereof, 2',5'-dihydroxy-4'-methoxyacetophenone and a pharmaceutically acceptable salt or ester thereof.

Description

FORMULATION FOR THE TREATMENT OF BENIGN PROSTATE HYPERPLASIA

The present invention relates to formulations for the treatment of benign prostate hyperplasia in humans.

Benign prostatic hyperplasia (BPH) is a condition affecting the prostate gland, a gland in the male reproductive system of most mammals, including human males. BPH is also sometimes known as benign enlargement of the prostate (BEP) , adenofibromyomatous hyperplasia, and benign prostate hypertrophy (although technically BPH involves hyperplasia rather than hypertrophy. In the present application the term "BPH" is intended to cover all of these conditions.

BPH involves hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of the prostate; thus, BPH results in an enlargement of the prostate. When sufficiently large, this enlargement can compress the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra. This can interfere with the normal flow of urine, leading to symptoms of urinary hesitancy, frequent urination, dysuria (painful urination) , increased risk of urinary tract infections, and urinary retention.

According to conventional medical thinking, BPH is not considered to be a premalignant lesion. However, prostate specific antigen levels may be elevated, it is believed because of increased organ volume and inflammation due to urinary tract infections. BPH occurs in a significant proportion of human males: an estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. In 40-50% of these patients, BPH becomes clinically significant. In addition, BPH can be a progressive disease, especially if left untreated .

BPH symptoms can be classified as either "storage" or "voiding". Storage symptoms include frequency of urination ("frequency") , compelling need to urinate ("urgency") , urgency incontinence, and nocturia (need to get up in the night to urinate) . Voiding symptoms include poor urinary stream, a need to wait before urination starts ("hesitancy") , having an intermittent stream, dysuria, needing to strain to void and dribbling, incomplete voiding, and terminal dribbling .

The symptoms of BPH are evaluated by using a questionnaire to measure the International Prostate Symptom Score (IPSS) - a score designed to assess the severity of BPH. This questionnaire and score were created by the American Urological Association (AUA) and is the most widely accepted means of evaluating the severity of BPH. The IPSS questionnaire comprises 8 questions: 7 symptom questions and 1 quality of life question. Each symptom question is scored on a scale of 0 to 5, 0 designating "not at all" and 5 designating "almost always" or "more than 5 times". Thus, the IPSS score may range from 0 to 35. The scores can be categorised as follows: Score Category

0-7 Mildly symptomatic

8-19 Moderately symptomatic

20-35 Severely symptomatic

The quality of life question states: "If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that"; the answer is a score of 0 (delighted) to 6 (terrible) .

Diagnosis of BPH can be made through a combination of evaluating the IPSS (to determine the severity of various symptoms of BPH) , rectal examination, and blood tests to determine prostate specific antigen (PSA) levels to rule out prostatic malignancy. As mentioned above, BPH can also result in elevated levels of PSA. What constitutes a normal PSA score depends on the age of the patient, although less than 4ng/ml is considered to be low risk (i.e. normal) and 4- lOng/ml is considered to be suspicious.

Depending on its severity, BPH can result in a significantly lowered quality of life and can necessitate intrusive lifestyle management (e.g. behavioural modification) . There is therefore a need for medicaments for treatment of the underlying causes and/or symptoms of BPH.

At present there are two main categories of medications available: alpha blockers and 5a-reductase inhibitors.

Alpha blockers used for BPH include doxazosin, terazosin, alfuzosin, tamsulosin, and silodosin. These drugs relax the smooth muscle in the prostate and bladder neck, thereby decreasing the blockage of urine flow; they treat the symptoms of BPH rather than treating the underlying cause. Common side effects of alpha blockers include orthostatic hypotension, ejaculation changes, nasal congestion, and weakness . 5a-reductase inhibitors include finasteride and dutasteride. These drugs inhibit the production of dihydrotestosterone (DHT) , a hormone responsible for enlarging the prostate. Side effects of these drugs include decreased libido and ejaculatory or erectile dysfunction.

In addition to the drug therapies, minimally invasive therapies and surgical treatments are also available.

Thus, there is a need for compositions which can treat the symptoms and/or underlying causes of BPH which do not suffer from the undesirable side effects produced by the presently- available drug therapies.

According to the present invention there is provided a composition for (use in) the treatment, amelioration and/or prevention of benign prostate hyperplasia (BPH) , the composition comprising apocynin, or a pharmaceutically acceptable salt or ester thereof, and paeonol, or a pharmaceutically acceptable salt or ester thereof. The composition may be a pharmaceutical preparation for (use in) the treatment of BPH.

Further, according to the present invention there is provided a method of treatment of BPH, comprising the step of administration (e.g. to a human or non-human animal subject in need thereof) of a composition, e.g. a therapeutically effective amount of a composition, comprising apocynin, or a pharmaceutically acceptable salt or ester thereof, and paeonol, or a pharmaceutically acceptable salt or ester thereof .

Further, according to the present invention there is provided a method of preventing BPH (e.g. a prophylactic method), comprising administering a therapeutically effective amount of a composition comprising apocynin and paeonol.

In this application, "treatment of" or "treating" benign prostate hyperplasia is intended to mean treatment/treating or amelioration of the benign prostate hyperplasia (in the sense treating the enlarged prostate itself) and/or treatment/treating or amelioration of the symptoms caused by (or associated with) BPH. These symptoms include, but are not limited to, lower urinary tract symptoms (LUTS) , such as frequency, urgency, dysuria, nocturia, poor stream, hesitancy, terminal dribbling, incomplete voiding, and overflow incontinence. Compositions of the present invention may also be used in the prevention of BPH. "Prevention" or "preventing" BPH is intended to mean preventing BPH itself and/or preventing the symptoms caused by (or associated with) BPH. It has surprisingly been found that compositions according to the present invention are particularly effective at treating and/or preventing benign prostate hyperplasia. This is demonstrated in the Examples described herein, in which it can be seen that the symptoms associated with BPH are lessened following administration of compositions according to the present invention, notably leading to a marked reduction in IPSS values. Apocynin is a plant phenol 4-hydroxy-3-methoxyacetophenone, nd has the following formula:

H₃

Apocynin is found in plant substances and plant extracts, for example in extracts of the plants picrorrhiza kurroa, apocynum cannabinium, apocynum venatum, apocynum androsaemifolium and vanilla species such as Vanilla planifolia . The compositions and preparations of the invention may include "isolated" apocynin. Isolated apocynin is apocynin which has been synthesised, or which has been extracted from plants and purified. Alternatively or additionally, apocynin may be present in compositions or preparations according to the invention as direct extracts from plants such as those mentioned above (for example as part of an unresolved mixture of compounds in the form of an unpurified plant or root extract) . These will be referred to as apocynin "in the natural form" or "natural apocynin". For example, apocynin present in preparations according to the invention in the form of picrorrhiza kurroa will be referred to as "natural apocynin". The term "natural apocynin" or apocynin "in the natural form" also includes glycosides of apocynin such as those found in the plant species in which apocynin is found. Such glycosides include androsin and other iridoid glycosides, for example. Preferably, the composition includes apocynin in a purified or synthetic form: "isolated" apocynin.

The composition may include apocynin as part of an unresolved mixture of compounds in the form of an unpurified plant or root extract: "natural" apocynin. The use of active entity in the natural form in combination with the isolated active apocynin may lead to a synergistic effect between the isolated form (e.g. purified or synthetic apocynin) and the natural form (e.g. apocynin included in picrorrhiza kurroa) . The preferred picrorrhiza kurroa is a standardised form based on standardised iridoid glucoside fraction, such forms are well known. A preferred picrorrhiza kurroa in standardised form comprises picrorrhiza kurroa standardised to "Kutkin min 4 "6 ". Standardised iridoid glucoside fractions between Kutkin min 2% and Kutkin min 8% are also preferred. In the Examples below, the picrorrhiza kurroa in standardised form comprises standardised iridoid glucoside fractions collectively known as "Kutkin min 2%". Kutkin is obtained by crystallization and consists of the glucosides picroside I and kutoside in a ratio of 1:2 and other minor glycoside (Sing and Rastogi, 1972, Ansari et al . , 1988) .

As indicated above, the composition may include apocynin which is in the natural form only, for example, picrorrhiza kurroa. However, if this is the case it may be necessary to limit the amount of picrorrhiza kurroa to prevent side effects (such as stomach upset which may occur due to other phytochemical species in the picrorrhiza kurroa) . However, it is noted that most human subjects can take up to 2,000 mg of picrorrhiza kurroa (Kutkin min 2%) per day without discomfort . Paeonol is 2-hydroxy-4-methoxy-acetophenone and is shown the following formula:

It may be found in plant substances and plant extracts.

For example paeonol may be found in Paeonia suffruticosa Paeonia lactiflora, Paeonia veitchii, Paeonia obovata, Cynanchum panniculatum, Rheum palmatum (rhizome) and Scutellaria baicalensis (root) .

The compositions and preparations of the invention may include "isolated" paeonol, that is paeonol which has been synthesised or paeonol which has been extracted from plants and purified. Paeonol may be present in preparations

according to the invention as direct extracts from plants (i.e. as part of an unresolved mixture of compounds in the form of an unpurified plant or root extract) . These will be referred to as paeonol "in the natural form" or "natural paeonol". For example, paeonol present in preparations according to the invention in the form of Paeonia

suffruticosa will be referred to as "natural paeonol". The terms paeonol "in the natural form" or "natural paeonol" include glycosides of paeonol such as those found in the plant species in which paeonol is found. Such glycosides include paeonin, paeonolide and paeonoside, for example.

Preferably the composition includes paeonol in a purified or synthetic form: "isolated" paeonol. In an alternative embodiment the paeonol may alternatively or additionally be present in natural form.

According to a further aspect of the present invention, in addition to, or instead of paeonol, the composition may comprise 2 ' , 4 ' -dihydroxyacetophenone and/or 2 ' , 5 ' -dihydroxy- 4 ' -methoxyacetophenone . These compounds share a common structural backbone to paeonol (2-hydroxy-4-methoxy- aceto henone) as can be seen in the structural formula below:

methoxyacetophenone

The inventor of the present invention has tested the above compounds, and has found that they also have anti- inflammatory properties. In particular, in in vitro tests 2 ', 5 ' -dihydroxy-4 ' -methoxyacetophenone displays anti^¬ inflammatory properties which are comparable to those of paeonol. Thus, it is believed that 2' , 5' -dihydroxy-4' - methoxyacetophenone could be used in place of, or in addition to, paeonol in compositions of the present invention.

Thus, according to a further aspect of the present invention there is provided a composition for (use in) the treatment, amelioration and/or prevention of benign prostate hyperplasia (BPH) , the composition comprising apocynin, or a pharmaceutically acceptable salt or ester thereof, and one or more compounds selected from the group consisting of paeonol, 2' , 4' -dihydroxyacetophenone, 2' , 5' -dihydroxy-4' - methoxyacetophenone and pharmaceutically acceptable salts or esters thereof. Such compositions may also be used in the methods of treatment and/or prevention described above with respect to compositions of the invention comprising apocynin (or a pharmaceutically acceptable salt or ester thereof) and paeonol (or a pharmaceutically acceptable salt or ester thereof) .

Preferably, according to one aspect of the present invention there is provided a composition for (use in) the treatment, amelioration and/or prevention of benign prostate hyperplasia (BPH) , comprising apocynin, or a pharmaceutically acceptable salt or ester thereof, paeonol, or a pharmaceutically acceptable salt or ester thereof, and 2 ' , 5 ' -dihydroxy-4 ' - methoxyacetophenone, or a pharmaceutically acceptable salt or ester thereof. Based on in vitro tests carried out by the inventor there is reason to believe that there may be a synergistic effect between the paeonol (or apocynin) and the 2 ' , 5 ' -dihydroxy-4 ' -methoxyacetophenone .

In the following description of the invention, there are provided a number of ratios and amounts of the various components of the present composition; the ratios and amounts are given for paeonol and apocynin (amongst other components) . In compositions of the present invention in which 2 4 ' -dihydroxyacetophenone and/or 2 5 ' -dihydroxy-4 ' - methoxyacetophenone are present, they may replace paeonol, or be added in addition to paeonol, in the same ratio and/or amounts set out in the passages below (i.e. for paeonol) . Alternatively, 2 4 ' -dihydroxyacetophenone and/or 2',5'- dihydroxy-4 ' -methoxyacetophenone may be present in an amount which is less than the amount of paeonol, e.g. from 0.1% to 50% , e.g. from 1% to 10%, e.g. from 1% to 5%, of the total amount of paeonol.

It is also believed that compositions comprising apocynin, or a pharmaceutically acceptable salt or ester thereof, and one or more compounds selected from the group consisting of paeonol, 2 ' , 4 ' -dihydroxyacetophenone, 2 ' , 5 ' -dihydroxy-4 ' - methoxyacetophenone and pharmaceutically acceptable salts or esters thereof, can be used to provide anti-inflammatory and/or analgesic formulations for the treatment of humans or animals (i.e. in therapeutic applications other than BPH) . In particular, it is believed that such formulations may be effective in treating inflammatory diseases such as inflammatory joint disease, arthritis and rheumatoid osteoarthritis, dermatitis, (atopic) dermatitis, sinusitis, hay-fever syndrome (allergic rhinitis, allergic lung diseases, inflammatory diseases of the gastro intestinal tract, such as ulcers (including stomach ulcers) , ulcerative colitis, gastric ulcer syndrome, celiac disease, irritable bowel syndrome, irritable bowel disease and Crohn's disease. They may be used to treat inflammatory diseases such as seasonal pruritic dermatitis, laminitis, eczematous dermatitis, COPD, lameness, azoturia, dermatitis, osteoarthritis, hip dysplasia and equine gastro ulcer syndrome of the sequellae thereof. The inflammatory disease may also be the treatment of inflammation or swelling, following, for example, injury or surgery (e.g. following an operation such as a hip replacement) . The treatment of inflammatory disease may include treatment of joint swelling.

In compositions of the present invention, the paeonol and/or apocynin (whether in isolated or natural form) may be incorporated as a pharmaceutically acceptable salt and/or ester. In particular, incorporating paeonol and/or apocynin in the form of an ester can result in the compound being more lipophilic (as opposed to the free form of these chemicals, which are more hydrophilic) , which can help the compound stay in the body for a greater duration, thus potentially extending period of efficacy of the composition.

Preferably, the composition according to the invention further comprises L-glutamine.

Preferably the composition according to the invention further comprises a filler. Preferred fillers include at least one flavonoid, preferably a mixture of one or more flavonoids. Preferred compositions further comprise glucosamine.

A preferred composition comprises apocynin and paeonol wherein the ratio (by weight) of apocynin to paeonol is between about 1 to 100 and about 100 to 1, preferably between about 10 to 1 and 1 to 30, more preferably between about 1 to 1 and 1 to 20, more preferably between about 1 to 2 and 1 to 10. Preferably the ratio (by weight) of apocynin to paeonol is 1 to 4. A preferred composition includes isolated apocynin and isolated paeonol and the ratio (by weight) of isolated apocynin to isolated paeonol is between 1:1 and 1:10, more preferably between 1:2 and 1:6 more preferably between 1:3 and 1:6, more preferably between 1:3 and 1:5, more preferably between 1:3 and 1:4. The composition may also include natural apocynin and/or natural paeonol. In the ratios above the weights of apocynin and paeonol refer to the weight of the components in the isolated form (e.g. isolated apocynin and isolated paeonol) . A preferred composition comprises apocynin and paeonol wherein apocynin is present in isolated form and in the natural form (e.g. picrorrhiza kurroa). Preferably the ratio (by weight) of isolated apocynin to apocynin in the natural form is between about 10 to 1 and 1 to 1 (based on a calculation where the natural apocynin is in the form of picrorrhiza kurroa standardised to Kutkin min 2%) .

A further preferred composition comprises apocynin and paeonol wherein apocynin is present in isolated form and paeonol is present in the isolated form and in the natural form (e.g. Paeonia suffruticosa) . Preferably the ratio (by weight) of isolated paeonol to paeonol in the natural form is between about 10 to 1 and 1 to 1, more preferably between 4:1 and 2:1 (based on a calculation where the natural paeonol is in the form of Paeonia suffruticosa as Moutan cortex) .

A preferred composition comprises apocynin and paeonol wherein apocynin is present in isolated form and in the natural form (e.g. picrorrhiza kurroa); and paeonol is present in isolated form and in the natural form (e.g. paeonia suffruticosa) .

Preferably the composition includes one or both of paeonol and apocynin in isolated form.

If the composition includes apocynin which is only in the natural form (that is no isolated apocynin) and paeonol which is only in the natural form (that is no isolated paeonol) , it is preferred that the % by weight of the total composition which is apocynin in the natural form (e.g. picrorrhiza kurroa) is at least 2.5% (more preferably at least 5%); and/or the % by weight of the total composition which is paeonol in the natural form (e.g. paeonia suffruticosa) is at least 2.5% (more preferably at least 5%) .

It is preferred that compositions of the present invention that contain Picrorrhiza kurroa (e.g. apocynin only in the form of Picrorrhiza kurroa) do not include Glycyrrhiza glabra in the ratio of Glycyrrhiza glabra : Picrorrhiza kurroa of between 2:1 and 1:3 by weight. More preferably, compositions of the present invention that contain Picrorrhiza kurroa (e.g. apocynin only in the form of Picrorrhiza kurroa) do not include Glycyrrhiza glabra. More preferably, compositions of the present invention do not contain Glycyrrhiza glabra.

Preferred compositions further comprise L-glutamine at a ratio (by weight) of apocynin to L-glutamine of between 40 to 1 and 1 to 40, more preferably between 1 to 10 and 1 to 40, more preferably between about 1 to 15 and 1 to 25. In another embodiment the ratio (by weight) of apocynin to L-glutamine is between about 10 to 1 and 1 to 10, more preferably between 5 to 1 and 1 to 5, more preferably between 2.5 to 1 and 1 to 1. Preferably the ratio (by weight) of apocynin to L- glutamine is about 1.875 to 1.

Preferred compositions may comprise L-glutamine at a ratio (by weight) of paeonol to L-glutamine of between 100 to 1 and 1 to 100, more preferably between about 40 to 1 and 1 to 1, more preferably between about 10 to 1 and 1 to 1, more preferably between about 8 to 1 and 5 to 1. Preferably the ratio (by weight) of paeonol to L-glutamine is about 7.5 to 1.

Preferred compositions may further comprise glucosamine, preferably at a ratio (by weight of apocynin to glucosamine) of between 1 to 10 and 1 to 40, more preferably between about 1 to 15 and 1 to 25.

Preferred compositions may further comprise methyl sulphonyl methane (MSM) , preferably at a ratio (by weight of apocynin to MSM) of between 1 to 10 and 1 to 40, more preferably between about 1 to 15 and 1 to 25.

Preferably the composition further includes a binder.

The compositions may be used as pharmaceutical preparations, for the treatment of BPH in humans, or veterinary preparations, for the treatment of BPH in non-human animals, e.g. mammals. In particular, the compositions may be used as veterinary preparations for the treatment of BPH in dogs.

The preparations (or compositions) may further comprise additional components such as pharmaceutically conventional carriers, diluents, flavourings, emulsifiers and stabilisers. They may comprise additional components (for example carriers or diluents) which are "conventional" in herbal remedies. Preferably the pharmaceutical or veterinary preparation (or composition) further comprises one or more of the following: [1] an agent to enhance the immune system, for example lactoferrin which has antiviral antibacterial and antioxidant effects ; [2] a natural source of vitamins such as bee pollen;

[3] a source, for example a natural source, of vitamins, minerals and amino acids, for example chlorella;

[4] a source of trace elements, for example chromium and/or vanadium and/or copper and/or zinc and/or manganese

[5] taste masking agents, for example yoghurt, fruit juice, honey and syrup.

The compositions and pharmaceutical/veterinary preparations may be suitable for oral administration. The methods of formulation of the compositions for oral administration are well known in the art. For example, the composition for administration may be prepared using a pharmaceutically acceptable carrier in a form suitable for administration. Such a carrier can be prepared as a tablet, a pill, a sugar- coated agent, a capsule, a liquid, a gel, a syrup, a slurry, a suspension, etc. The carrier may be a herbal binder or one or more pharmaceutically acceptable carriers such as liposomes, lactose, trehalose, sucrose, mannitol, xylitol, crystalline cellulose, chitosan, calcium carbonate, talc, titanium oxide, or silica (silicon oxide) or the like.

The composition may be obtained, for example, by combining the active ingredients with a solid excipient, pulverizing the mixture (if necessary) and inserting into a capsule, for example, a soft sealed capsule consisting of a gelatin capsule, gelatin and coating (e.g., glycerol or sorbitol) or a capsule composition suitable for vegetarians. In the soft capsule, the composition may be dissolved or suspended in an appropriate liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol, with or without a stabilizer.

The formulation (composition or preparation) may also be in the form of a standardised liquid extract. Standardised liquid extracts may in some circumstances have advantages when compared to the solid dose forms (tablets and hard shell capsules) . They may involve minimal processing during manufacture during manufacture and may reflect the true spectrum of the original herb (or plant etc.), in a compact and convenient form. There is also the possibility of superior bioavailability as the preparation is already in the liquid form. The prescribed dose may then be easily diluted (water, fruit juice, adding ice etc.) so as to minimise the experience of any unpleasant taste thus increasing the likelihood of patient compliance.

Compositions of the invention may also be formulated as preparations that are suitable for other means of administration, for example mucosal delivery routes (for example rectal, nasal, vaginal) and also topical administration. The methods of formulation of the compositions for use in these methods are well known in the art. For example, the composition may be formulated as a cream and/or ointment, e.g. for topical application.

Compositions of the invention may be formulated as sustained and/or delayed release formulations, as is known in the art. Sustained release dosage forms are designed to release the active ingredients at a predetermined rate, thereby maintaining a constant level of active ingredients for a specific period of time. In delayed release dosage forms, there is a time delay before the active ingredients begin to be absorbed by the body. The advantages of sustained release formulations, as well as the methods and materials for creating such formulations, are well understood in the art. The inventor has found that apocynin and paeonol are absorbed by the body over a relatively short time period; thus, it may be particularly advantageous to formulate compositions of the present invention as sustained and/or delayed release formulations . The compositions and preparations may be used as (or in the manufacture of) pharmaceuticals for the treatment of BPH in human subjects. They may also be used as (or in the manufacture of) veterinary preparations for the treatment of BPH in non-human animals, for example dogs.

According to the present invention in a further aspect, there is provided the use of apocynin and paeonol in (or in the manufacture of) a preparation for the treatment of benign prostate hyperplasia.

Preferably the preparation (or composition) is administered to a subject (human or animal) at a concentration, per daily dose, of apocynin, of between 0.5mg/kg body weight and 50mg/kg body weight, more preferably 1 to 8mg/kg body weight, more preferably 2 to 6mg/kg body weight. Preferably, the preparation is administered to a human or animal subject at a concentration, per daily dose, of paeonol of lmg/kg body weight to 70mg/kg body weight, more preferably between about 5mg/kg and 45mg/kg body weight, more preferably between about 9mg/kg and 24mg/kg body weight. These daily dose concentrations are based on isolated apocynin and isolated paeonol . The above daily doses may be reduced to 50% of the above values after a period of prolonged administration; for example, the daily doses may be gradually reduced from 100% to 50% of the above values. The above daily doses may also be doubled during the initial period of adminstration (e.g. until symptoms of BPH are reduced by a satisfactory degree) ; subsequently, the double daily dose may be gradually reduced from double to 100% of the above values. In a preferred embodiment the preparation (or composition) is administered to a subject (e.g. human) at a concentration, per daily dose, of isolated apocynin, of between 0.5mg/kg body weight and 50mg/kg body weight, more preferably 1 to 8mg/kg body weight, more preferably 2 to 6mg/kg body weight. Preferably, the preparation is administered to a subject at a concentration, per daily dose, of isolated paeonol of lmg/kg body weight to 70mg/kg body weight, more preferably between about 5mg/kg and 45mg/kg body weight, more preferably between about 9mg/kg and 24mg/kg body weight. The preparation may further comprise natural paeonol (e.g. paeonia suffruticosa, e.g. in the form of Moutan cortex) and is administered to a subject (e.g. human) at a concentration, per daily dose, of natural paeonol, of between lmg/kg body weight and 50mg/kg body weight, more preferably 4 to 8mg/kg body weight.

Preferably, the preparation (or composition) further comprises apocynin, in the natural form, and is administered to the subject at a concentration, per daily dose, of natural apocynin, of between 0.25 mg/kg and 15 m/kg, more preferably 1 to 3 mg/kg.

The doses may be increased (e.g. doubled) at the beginning of the treatment, for example for the first 1 to 3 days, as a "loading dose". Thus, as a loading dose, the preparation (or composition) may be administered to a subject (human or animal) at a concentration, per daily dose, of apocynin, of between lmg/kg body weight and lOOmg/kg body weight, more preferably 5 to 16mg/kg body weight. Preferably, the preparation is administered to a human or animal subject at a loading dose concentration, per daily dose, of paeonol of 5mg/kg body weight to 140mg/kg body weight, more preferably between about lOmg/kg and 90mg/kg body weight, more preferably between about 15mg/kg and 50mg/kg body weight. These daily dose concentrations are based on isolated apocynin and isolated paeonol.

Preferably, the preparation (or composition) further comprises L-glutamine and/or Glucosamine and one or both are administered to the subject at a concentration, per daily dose, of L-glutamine and/or glucosamine of 0.5mg/kg body weight to 280mg/kg body weight, more preferably lmg/kg body weight to 50mg/kg body weight, more preferably between lmg/kg body weight and lOmg/kg body weight, more preferably between 1.25mg/kg body weight and 3.5mg/kg body weight.

The daily dose may be provided as a single capsule, tablet or other solid or liquid form known to those skilled in the art, or may be provided in divided doses (for example 1 to 4 doses) to make up the full daily dose. The doses of apocynin and paeonol may be provided together in the capsule, tablet, etc. or the two may be provided as separate capsules or tablets for sequential administration.

According to the present invention in a further aspect, there is provided kit of parts for a preparation for (use in) the treatment or prevention of BPH comprising at least one dose of apocynin; and at least one dose of paeonol. It is envisaged that the kit of parts may be provided as, for example, a blister pack containing capsules containing doses or partial doses, for example, apocynin, and separate capsules containing doses or partial doses of paeonol. The pack may be provided with instructions for sequential administration of the doses. When administered either together or separately the compounds should be administered such as to maintain a suitable blood level of each of the components. When administered separately the compounds

(apocynin and paeonol) should be given within 4 hours of each other, preferably within 2 hours, and most preferably substantially simultaneously. It is preferred that the preparation is administered orally, for example, in pill or capsule form, although it is possible to use other known conventional administration techniques.

According to the present invention in a still further aspect there is provided a method of treatment of BPH comprising a step of administration to a human or non-human animal subject in need thereof of a composition comprising apocynin and paeonol. According to the present invention in a still further aspect there is provided the use, in the manufacture of a preparation for the treatment of BPH, of apocynin and paeonol .

Preferably the composition/preparation includes apocynin in isolated form.

Preferably the composition/preparation includes paeonol in isolated form. The compositions, preparations and doses according to the invention may include other components which have effects in treatment of BPH. However, it is preferred that the paeonol and the apocynin (in isolated form and/or in natural form) represent (or lead to) substantially all of the BPH-treating activity of the compositions, preparations and doses.

The compositions, preparations, methods and uses may be used in combination with other (conventional) medicaments or preparations .

The present invention will now be described in detail with reference to illustrative examples.

EXAMPLE 1

The following components are mixed in a conventional manner:

In the following examples the above composition is referred to as "Example 1" or "APPA mix".

EXAMPLE 2

The following components are mixed in a conventional manner:

EXAMPLE 2

L-glutamine 50mg

Glucosamine 50mg Moutan cortex

( Paonia

suffruticosa) lOOmg

Paeonol

(isolated) 350mg

Apocynin

(isolated) lOOmg

Total 650mg

This mix packs into a type ^Λ0' capsule (650mg in total) and is taken (based on a human of body weight 60 to 80kg) at a rate of two such capsules twice per day: am and pm. In exceptional cases the dose may be increased at the beginning of treatment, (e.g. doubled for the first 1 to 3 days) .

In the following examples, the acronym BID refers to bis in die (i.e. twice-a-day) ; the acronym SID refers to once-a-day.

Example A

Human 63 yo male with gross degeneration of L3-L5 as well as L5-S1 thought that these degenerative lumbar problems might be related to his long term history of increased urinary frequency and nocturnal urination. BPH was diagnosed, and the patient score 10 on the AUA/IPSS Symptom Index Questionnaire. APPA Mix (2x 500mg am, 1 x 500mg pm) was administered. At 48 hours the patient noted an improved urinary flow and diminished urinary frequency during the night. After four weeks the patient's AUA/IPSS Symptom Index Questionnaire score was 2. The patient continues APPA Mix (500mg BID) .

Example B

Human 68 yo male with a history of prostatic hyperplasia concomitant with a small undefined tumour area (following repeated biopsies and imaging procedures) . Patient had consistently high PSA levels averaging between 10-11 ng/ml over a 3 year period. Patient had an AUA/IPSS Symptom Index Questionnaire score of 18. APPA Mix (2 x 500mg SID - am) was administered. At 72 hours the patient reported a stronger urinary flow and diminished urinary frequency during the night. The patient reported that when he drank "too much red wine", although nocturnal urinary flow was stronger than before he still had to get up to urinate more often (2- 3/night vs 1/night with APPA Mix) . After four weeks the patient's AUA/IPSS Symptom Index Questionnaire score was 9. The patient's PSA level decreased to 5.6 ng/ml. The patient was been advised to increase the APPA Mix to 2 x 500mg BID. After eight weeks from initial treatment the patient's AUA/IPSS Symptom Index Questionnaire score was 5.

Example C

Human 60 yo male with BPH. AUA/IPSS Symptom Index Questionnaire score was 9. APPA Mix (2x 500mg am, 1 x 500mg pm) was administered. At 48 hours the patient reported that he was now urinating normally and sleeping through the night. At 4 weeks the patient's AUA/IPSS Symptom Index Questionnaire score was 2. The patient continues with APPA Mix (2x 500mg am, 1 x 500mg pm) .

Example D

Human 65 yo male with BPH. AUA/IPSS Symptom Index Questionnaire score was 12. APPA Mix (2x 500mg am, 1 x 500mg pm) was administered. At 48 hours the patient reported that "everything seemed to be working as well as it was years ago". At 4 weeks the patient's AUA/IPSS Symptom Index Questionnaire score was 3. The patient continues with APPA Mix (2x 500mg am, 1 x 500mg pm) .

Claims

C L A I M S :

1. A composition for use in the treatment of benign prostate hyperplasia, the composition comprising apocynin, or a pharmaceutically acceptable salt or ester thereof, and one or more compounds selected from the group consisting of paeonol, a pharmaceutically acceptable salt or ester thereof, 2 ' , 5' -dihydroxy-4 ' -methoxyacetophenone, and a pharmaceutically acceptable salt or ester thereof.

2. A composition for use according to claim 1, comprising apocynin, or a pharmaceutically acceptable salt or ester thereof, and paeonol, or a pharmaceutically acceptable salt or ester thereof.

3. A composition for use according to claim 1 or 2, comprising apocynin in the form of isolated apocynin.

4. A composition for use according to and of claim 1 to 3 comprising apocynin in the form of natural apocynin.

5. A composition for use according to claim 4 wherein the natural apocynin is one or more of picrorrhiza kurroa, apocynum cannabinium, apocynum venatum, apocynum androsaemifolium, or vanilla species such as Vanilla planifolia, or extract (s) thereof, or is an apocynin glycoside .

6. A composition for use according to any of claims 2 to 5 comprising paeonol in the form of isolated paeonol.

7. A composition for use according to any of claims 2 to 6 comprising paeonol in the form of natural paeonol.

8. A composition for use according to claim 7 wherein the natural paeonol is one or more of Paeonia suffruticosa a, Paeonia lactiflora, Paeonia veitchii, Paeonia obovata,

Cynanchum panniculatum, Rheum palmatum or Scutellaria

baicalensis, or extract thereof, or is a paeonol glycoside.

9. A composition for use according to any preceding claim further comprising L-glutamine.

10. A composition for use according to any preceding claim further comprising methyl sulphonyl methane.

11. A composition for use according to any preceding claim further comprising a filler.

12. A composition for use according to claim 11 wherein the filler includes at least one flavonoid.

13. A composition for use according to any of claims 2 to 12 wherein the ratio (by weight) of apocynin to paeonol is between about 1 to 100 and about 100 to 1.

14. A composition for use according to any of claims 2 to 13 wherein the ratio (by weight) of apocynin to paeonol is between about 1 to 1 and 1 to 20.

15. A composition for use according to any of claims 2 to 15 wherein the ratio (by weight) of apocynin to paeonol is about 1 to 4.

16. A composition for use according to any preceding claim wherein apocynin is present in the isolated form and in the natural form and the ratio (by weight) of isolated apocynin to apocynin in the natural form is between about 10 to 1 and 1 to 1.

17. A pharmaceutical or veterinary preparation for use in the treatment of benign prostate hyperplasia, the preparation comprising a composition for use according to any preceding claim.

18. A pharmaceutical or veterinary composition for use in the treatment of benign prostate hyperplasia, the composition comprising a unitary dose of isolated apocynin, or a pharmaceutically acceptable salt or ester thereof, equivalent to between 0.5mg/kg body weight and 50mg/kg body weight; and a unitary dose of paeonol, or a pharmaceutically acceptable salt or ester thereof, equivalent to between lmg/kg body weight and 70mg/kg body weight.

19. A composition for use according to claim 18 wherein the unitary dose of isolated apocynin, or the pharmaceutically acceptable salt or ester thereof, is equivalent to between 1 and 8mg/kg body weight.

20. A composition for use according to claim 18 or 19 wherein the unitary dose of paeonol, or the pharmaceutically acceptable salt or ester thereof, is between about 4 and 24mg/kg body weight.

21. A composition according to any of claims 18 to 20 further comprising apocynin in the natural form; wherein the unitary dose of natural apocynin is between 0.25 mg/kg and 15 mg/kg, more preferably 1 to 3 mg/kg.

22. A kit of parts for a preparation for treatment of benign prostate hyperplasia, comprising at least one dose of apocynin, or a pharmaceutically acceptable salt or ester thereof; and at least one dose of paeonol, or a pharmaceutically acceptable salt or ester thereof.

23. The use of apocynin, or a pharmaceutically acceptable salt or ester thereof, and paeonol, or a pharmaceutically acceptable salt or ester thereof, in a preparation for the treatment of benign prostate hyperplasia.

24. A method of treatment of benign prostate hyperplasia comprising a step of administration, to a human or non-human animal subject in need thereof, of a composition comprising apocynin, or a pharmaceutically acceptable salt or ester thereof, and one or more compounds selected from the group consisting of paeonol, a pharmaceutically acceptable salt or ester thereof, 2 ' , 5 ' -dihydroxy-4 ' -methoxyacetophenone and a pharmaceutically acceptable salt or ester thereof.

25. A method of treatment according to claim 24, in which the composition comprises apocynin, or a pharmaceutically acceptable salt or ester thereof, and paeonol, or a pharmaceutically acceptable salt or ester thereof.

26. A method according to claim 25 in which the apocynin is administered to the subject at a daily dose equivalent to between lmg/kg body weight and 50mg/kg body weight isolated apocynin; and the paeonol is administered to the subject at a daily dose equivalent to between lmg/kg body weight and 70mg/kg body weight isolated paeonol.

27. A composition for use according to claim 18 wherein the daily dose of apocynin is equivalent to between 1 and 8mg/kg body weight (isolated apocynin) .

28. A composition for use according to claim 18 or 27 wherein the daily dose of paeonol is equivalent to between 4 and 24mg/kg body weight.

29. A composition for use in the treatment of benign prostate hyperplasia, the composition comprising L-glutamine ; paeonol; and apocynin in the ratio (parts by weight) 8 : 60 : 15.

30. A composition for use in the treatment of benign prostate hyperplasia, the composition comprising methyl sulphonyl methane; paeonol; and apocynin in the ratio (parts by weight) 8 : 60 : 15.

31. A composition for use in the treatment of benign prostate hyperplasia, the composition substantially as hereinbefore described with reference to Example 1.

32. The use, in the manufacture of a preparation for the treatment of benign prostate hyperplasia, of apocynin, or a pharmaceutically acceptable salt or ester thereof, and one or more compounds selected from the group consisting of paeonol, a pharmaceutically acceptable salt or ester thereof, 2',5'- dihydroxy-4 ' -methoxyacetophenone and a pharmaceutically acceptable salt or ester thereof.

33. A composition for use in the treatment of benign prostate hyperplasia, the composition substantially as hereinbefore described with reference to Example 2.

34. A composition for use in the treatment of benign prostate hyperplasia, the composition including L-glutamine, Glucosamine, natural paeonol, isolated paeonol, and isolated apocynin in the ratio (parts by weight) 50: 50: 100: 350: 100.